1. Technical Field
The present invention relates to novel cytosine compounds, and a process for the production thereof. More specifically, the present invention relates to the production of 2,3'-O-cyclocytidine, 2,3'-O-cyclocytidine analogues and pharmaceutically acceptable salts thereof using novel 3'-O-tosylcytidine precursor compounds and pharmaceutically acceptable salts thereof. The invention also relates to the production of 1-(.beta.-D-xylo-pentofuranosyl)cytosine, 1-(.beta.-D-xylo-pentofuranosyl)cytosine analogues and pharmaceutically acceptable salts thereof.
2. Brief Description of the Prior Art
Mizuno et al (Tet. Lett., 4579-4584 (1965)) teach the production of 2,3'-O-cyclocytidine via a six step process which includes the production of 3'-O-mesylcytidine via a four step process from N.sup.4 -acetylcytidine. This corresponds to a five step process, overall, if cytidine is used as the starting material. Thus, it is not surprising that the overall yield of 3'-O-mesylcytidine produced in this manner is less than 10% (even this low yield assumes theoretical yields for two of the five steps where yield was unreported).
Fromageot et al (Tet. Lett., 3499-3505, (1966)) speculated production of N.sup.4, O.sup.2', O.sup.5' -triacetyl-3-O'-tosylcytidine by reacting an equilibrium mixture of N.sup.4, O.sup.2', O.sup.5' -isomer with a slight excess of p-toluenesulfonyl chloride in an anhydrous pyridine solution. The 3'-O-tosylcytidine derivative was assumed to be a product present in a dichloromethane phase after an arabinofuranosylcytosine derivative had been extracted from the reaction mixture with water. However, the 3'-O-tosylcytidine derivative was not isolated nor is there any disclosure or suggestion of how to prepare this derivative.
Further, as taught in Mizuno et al (Tet. Lett., 4579-4584 (1965)), 2,3'-O-cyclocytidine is produced from 3'-O-mesylcytidine as a crystalline free-base. Specifically, the last step in the process comprises reacting 3'-O-mesylcytidine with an excess of sodium t-butoxide to produce 2,3'-O-cyclocytidine. Unfortunately, the first step in the process involved conversion of N.sup.4 -acetylcytidine (NOTE: this was obtained from cytidine in only a 65% yield) to 2',5'-di-O-trityl-N.sup.4 -acetylcytidine in only a 20% yield. Accordingly, the process of Mizuno et al is deficient in that it requires an onerous number of steps to produce 2,3'-O-cyclocytidine and, when produced, 2,3'-O-cyclocytidine is obtained in a relatively low yield of less than 8.5% (even this low yield assumes theoretical yields for two of the six steps where yield was unreported). Further, Doerr et al (J. Org. Chem., 32, 1462-1471 (1967)) found it surprising that Mizuno et al reported isolating 2,3'-O-cyclocytidine in neutral form.
Fox et al (J. Am. Chem. Soc., 29, 5060-5064 (1957)) teaches the production of 1-(.beta.-D-xylofuranosyl) cytosine via coupling of a 100% excess of protected xylosyl halide and protected mercuri-cytosine, followed by deprotection of the coupled compound to form 1-(.beta.-D-xylo-pentofuranosyl)cytosine. Unfortunately, the coupling step provided a product in only 23% yield which corresponds to an overall yield of 1-(.beta.-D-xylo-pentofuranosyl)cytosine of 18%. It will be appreciated that these yields would be even lower if they were based on xylose and cytosine as starting materials.
Gosselin et al (J. Med. Chem., 1986, 29, 203-213 ) teach the production of 1-.beta.-D-xylofuranosyl compounds by glycosylation of purine and pyrimidine aglycons with peracylated 1-O-acetyl-.alpha.-D-xylofuranoses, followed by removal of the blocking groups.
It would be desirable to have a relatively simply process for the production of 1-(.beta.-D-xylo-pentofuranosyl)cytosine compounds which did not comprise the use of blocking groups followed by removal of such blocking groups. It would also be desirable to have a more convenient process which provided higher or comparable yields of such 1-(.beta.-D-xylo-pentofuranosyl)cytosine compounds.